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Zmpste24  -  zinc metallopeptidase, STE24

Mus musculus

Synonyms: A530043O15Rik, CAAX prenyl protease 1 homolog, D030046F19, FACE-1, FACE1, ...
 
 
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Disease relevance of Zmpste24

 

High impact information on Zmpste24

  • Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase-deficient mice [4].
  • Lack of functional Zmpste24, a metalloproteinase responsible for the maturation of prelamin A, also results in progeroid phenotypes in mice and humans [5].
  • We found that Zmpste24-deficient mouse embryonic fibroblasts (MEFs) show increased DNA damage and chromosome aberrations and are more sensitive to DNA-damaging agents [5].
  • Bone marrow cells isolated from Zmpste24-/- mice show increased aneuploidy and the mice are more sensitive to DNA-damaging agents [5].
  • Zmpste24 deficiency results in the accumulation of prelamin A within cells, a complete loss of mature lamin A, and misshapen nuclear envelopes [2].
 

Chemical compound and disease context of Zmpste24

 

Biological context of Zmpste24

  • We demonstrate that Zmpste24 deficiency elicits a stress signalling pathway that is evidenced by a marked upregulation of p53 target genes, and accompanied by a senescence phenotype at the cellular level and accelerated ageing at the organismal level [7].
  • Remarkably, the presence of a single Lmna(LCO) allele eliminated the nuclear shape abnormalities and progeria-like disease phenotypes in Zmpste24-/- mice [8].
  • Prelamin A, Zmpste24, misshapen cell nuclei, and progeria--new evidence suggesting that protein farnesylation could be important for disease pathogenesis [9].
  • The recent findings involving the lamin A/FACE-1 (substrate/protease) system in the etiology of Hutchinson-Gilford progeria syndrome and related pathologies have shed some light on the mechanisms underlying the development of these devastating conditions [10].
  • The mouse genome contains orthologues for both yeast RCE1 and STE24 [11].
 

Anatomical context of Zmpste24

  • Prelamin A processing was defective both in fibroblasts lacking Zmpste24 and in fibroblasts lacking the CAAX carboxyl methyltransferase Icmt but was normal in fibroblasts lacking the CAAX endoprotease Rce1 [1].
  • Zmpste24 is an integral membrane metalloproteinase of the endoplasmic reticulum [1].
  • Zmpste24 is a metalloproteinase required for the processing of prelamin A to lamin A, a structural component of the nuclear lamina [2].
  • Since no natural substrates for mammalian Zmpste24 have been identified, yeast a-factor was used as a surrogate substrate to investigate the biochemical activities in membranes from the cells and tissues of Zmpste24-deficient mice [11].
  • MicroCT is also useful for studying osteoporosis in mice and phenotypes of mice with gene manipulation, such as SHIP-knockout mice, which are severely osteoporotic due to increased numbers of hyperresorptive osteoclasts, PTHrP heterozygous-null mice, and mice with Zmpste24 deficiency [12].
 

Other interactions of Zmpste24

  • Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation [7].
 

Analytical, diagnostic and therapeutic context of Zmpste24

  • In combination with information from chemical modifications and site-directed mutagenesis, the structural comparisons and sequence alignments suggest a multisite binding mode for toxin-receptor interactions, and three "toxic regions" with relevance to the binding process, including Face A, Face B, and Site C [13].

References

  1. Zmpste24 deficiency in mice causes spontaneous bone fractures, muscle weakness, and a prelamin A processing defect. Bergo, M.O., Gavino, B., Ross, J., Schmidt, W.K., Hong, C., Kendall, L.V., Mohr, A., Meta, M., Genant, H., Jiang, Y., Wisner, E.R., Van Bruggen, N., Carano, R.A., Michaelis, S., Griffey, S.M., Young, S.G. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  2. Heterozygosity for Lmna deficiency eliminates the progeria-like phenotypes in Zmpste24-deficient mice. Fong, L.G., Ng, J.K., Meta, M., Coté, N., Yang, S.H., Stewart, C.L., Sullivan, T., Burghardt, A., Majumdar, S., Reue, K., Bergo, M.O., Young, S.G. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  3. Hutchinson-Gilford progeria syndrome. Pollex, R.L., Hegele, R.A. Clin. Genet. (2004) [Pubmed]
  4. Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase-deficient mice. Pendás, A.M., Zhou, Z., Cadiñanos, J., Freije, J.M., Wang, J., Hultenby, K., Astudillo, A., Wernerson, A., Rodríguez, F., Tryggvason, K., López-Otín, C. Nat. Genet. (2002) [Pubmed]
  5. Genomic instability in laminopathy-based premature aging. Liu, B., Wang, J., Chan, K.M., Tjia, W.M., Deng, W., Guan, X., Huang, J.D., Li, K.M., Chau, P.Y., Chen, D.J., Pei, D., Pendas, A.M., Cadiñanos, J., López-Otín, C., Tse, H.F., Hutchison, C., Chen, J., Cao, Y., Cheah, K.S., Tryggvason, K., Zhou, Z. Nat. Med. (2005) [Pubmed]
  6. A protein farnesyltransferase inhibitor ameliorates disease in a mouse model of progeria. Fong, L.G., Frost, D., Meta, M., Qiao, X., Yang, S.H., Coffinier, C., Young, S.G. Science (2006) [Pubmed]
  7. Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation. Varela, I., Cadiñanos, J., Pendás, A.M., Gutiérrez-Fernández, A., Folgueras, A.R., Sánchez, L.M., Zhou, Z., Rodríguez, F.J., Stewart, C.L., Vega, J.A., Tryggvason, K., Freije, J.M., López-Otín, C. Nature (2005) [Pubmed]
  8. Prelamin A and lamin A appear to be dispensable in the nuclear lamina. Fong, L.G., Ng, J.K., Lammerding, J., Vickers, T.A., Meta, M., Coté, N., Gavino, B., Qiao, X., Chang, S.Y., Young, S.R., Yang, S.H., Stewart, C.L., Lee, R.T., Bennett, C.F., Bergo, M.O., Young, S.G. J. Clin. Invest. (2006) [Pubmed]
  9. Prelamin A, Zmpste24, misshapen cell nuclei, and progeria--new evidence suggesting that protein farnesylation could be important for disease pathogenesis. Young, S.G., Fong, L.G., Michaelis, S. J. Lipid Res. (2005) [Pubmed]
  10. From immature lamin to premature aging: molecular pathways and therapeutic opportunities. Cadiñanos, J., Varela, I., López-Otín, C., Freije, J.M. Cell Cycle (2005) [Pubmed]
  11. Biochemical studies of Zmpste24-deficient mice. Leung, G.K., Schmidt, W.K., Bergo, M.O., Gavino, B., Wong, D.H., Tam, A., Ashby, M.N., Michaelis, S., Young, S.G. J. Biol. Chem. (2001) [Pubmed]
  12. Application of micro-CT assessment of 3-D bone microstructure in preclinical and clinical studies. Jiang, Y., Zhao, J., Liao, E.Y., Dai, R.C., Wu, X.P., Genant, H.K. J. Bone Miner. Metab. (2005) [Pubmed]
  13. A series of bioactivity-variant neurotoxins from scorpion Buthus martensii Karsch: X-ray crystal structure and functional implications. Wang, D.C. Journal of natural toxins. (1999) [Pubmed]
 
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